Source of Support: This study was supported by a grant from Scientific and Research Project of Health and Family Planning Committee of Sichuan Province of China (No. 150008); a grant from Science and Technology Department of Sichuan Province of China (No. 2016JY0248); and a grant from Medical Science Research Project of Sichuan Province of China (No. S15009)., Conflict of Interest: None

Check

DOI: 10.4103/2468-5577.187076

Abstract

Background: Migraine is a global disease with a high morbidity rate, and while there is medication for migraine prevention, it has many side effects. Thus there is a need to find a non-drug therapy to prevent migraine in patients with frequent attacks of migraine, severe pain, and poor drug control. Cortical spreading depression (CSD) is an important pathological mechanism behind migraine. Electrical fastigial nucleus stimulation (FNS) can reportedly inhibit the occurrence and propagation of CSD, and therefore can be used to prevent migraine. Methods/Design: This is a prospective, multi-center, randomized, double-blind, sham-controlled trial. It will be performed at Chengdu Second People's Hospital, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Fourth People's Hospital, the First Affiliated Hospital of Chongqing Medical University, and Chongqing People's Hospital, China. The approach is to randomly allocate 80 eligible migraine patients to undergo 3 months of either noninvasive electrical FNS (pulse width 90 μs, frequency 1.8 kHz, and output current 10 mA) or ineffective sham-stimulation (using the same stimulation equipment; pulse width 90 μs, frequency 10 kHz, and output current 0.18 mA). The primary outcomes are: change in monthly migraine days between the run-in month and 3 rd month of treatment, and percentage of patients having at least a 50% reduction of monthly migraine days in the 3 rd month of treatment. The secondary outcomes are: change between average monthly migraine days across 3 months of treatment and monthly migraine days in the 3 rd month of treatment, Visual Analogue Scale score in the 3 rd month of treatment, change in monthly anti-migraine drug use between the run-in month and 3 rd month of treatment, migraine disability assessment questionnaire score, accompanying symptoms, and adverse reactions. Discussion: In previous studies on electrical FNS for the treatment of various brain injuries, sample sizes have been small with inclusion of only a small number of institutions and non-rigorous trial protocols. Accordingly, the data obtained were not very reliable. In this study, we will validate the efficacy of electrical FNS in migraine prevention using a multi-center, randomized, double-blinded, controlled trial. Our findings will provide evidence for clinical application of this method.Trial registration: The trial protocol was registered at Chinese Clinical Trial Registry (www.chictr.org.cn) (registration number: ChiCTR-ICR-15006273) on 5 April 2015. Ethics: This trial was approved by the Ethics Committee of Chengdu Second People's Hospital, China on 9 April 2015 (approval number: 2015010), and will be performed in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.Informed consent: Written informed consent will be obtained from participants or their guardians.

Migraine is a primary pain characterized by recurrent episodes of moderate to severe headache. The pain generally affects one side of the head, is pulsating, lasts for 4-72 hours, is often accompanied by nausea, vomiting, and sensitivity to light, sound or smell, and is worsened after physical activity (Headache Classification Subcommittee of the International Headache Society, 2004). Global prevalence of migraine is appropriately 15%, with approximately 100 million people worldwide affected (Vos et al., 2012) and a higher prevalence in females than males (19% vs. 11%) (Vos et al., 2012). Moreover, migraine prevalence in Asian populations is lower than in European and American, but is still over 10% (Wang, 2003). Anti-epileptic drugs, antidepressants, calcium antagonists, and β-receptor blockers reduce the frequency and intensity of migraines (Gilmore and Michael, 2011; Jackson et al., 2012; Loder et al., 2012; Silberstein et al., 2012; Shamliyan et al., 2013). However, their use is limited because of strict medication times and high costs (Lipton et al., 2001), as well as potential adverse reactions including myocardial ischemia, disturbed sleep, sexual dysfunction, dry mouth, obesity, tremor, hair loss, and fetal birth defects (Silberstein et al., 2004; Bartleson and Cutrer, 2010; Gilmore and Michael, 2011). In addition, ergotamine overdose may increase migraine frequency and intensity (Headache Classification Subcommittee of the International Headache Society, 2004; Tepper and Tepper, 2010). Thus, migraine patients have to weigh the adverse reactions of several drugs against repeated headache episodes. For migraine patients with frequent attacks, intense pain, and poor drug control, non-drug measures may help prevent migraine.

The pathological mechanism underlying migraine remains poorly understood, but most authors assume that cortical spreading depression (CSD) and trigeminal nerve vasculitis co-mediate the occurrence of migraine. CSD refers to the phenomenon of neuronal activation followed by inhibition, specifically, neurons propagate on the cortical surface at 2-5 mm/min for 15-30 minutes, leading to destruction of cellular ionic gradients and resulting in inhibition of neuronal activity. An imaging study confirmed the changes in cerebral blood flow and cerebral activity in patients with migraine (with or without aura), which suggest the presence of CSD (Sprenger and Borsook, 2012). CSD activates the trigeminal vascular system, increases sensitivity, and consequently initiates a series of nerve, vascular and inflammatory events that finally induce migraine (Gasparini et al., 2013; Karatas et al., 2013; Cui et al., 2014). As a pathogenic factor, CSD likely plays a key role in the occurrence of migraine. Therefore, FNS for CSD and inflammation inhibition can theoretically prevent migraine. Previous observational studies have demonstrated that non-invasive FNS prevents migraines with good safety (Huo and Yu, 2001; Lin et al., 2002; Wang et al., 2007). However, in these studies, the sample sizes are small, only a few institutions are included, and the trial protocol is not rigorous enough. Consequently, the data obtained are not reliable.

In this study, we will validate the efficacy of electrical cerebellar FNS for the prevention of migraine using a multi-center, randomized, double-blinded placebo-controlled trial.

Methods/Design

Study design

A multi-center, randomized, double-blind, sham-controlled trial.

Study setting

The trial will be performed at Chengdu Second People's Hospital, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Fourth People's Hospital, the First Affiliated Hospital of Chongqing Medical University, and Chongqing People's Hospital, China.

Study procedure

The study is designed to validate the efficacy and safety of non-invasive FNS on prevention of migraine. Patients with migraine were screened against our inclusion and exclusion criteria (see below). Eighty eligible patients were randomly allocated to FNS and sham-stimulation groups. The flow chart of the trial protocol is shown in [Figure 1].

Patients will be withdrawn from the trial because of any of the following conditions:

Patients do not meet the inclusion criteria but conform to the exclusion criteria and are recruited because of errors

Patients do not receive treatment according to the therapeutic regimen or cannot provide complete information

Patients cannot participate in the trial because of severe adverse events

Patients need to take emergency measures because of complications or a worsened pathological condition

Poor patient compliance, and consequently receive treatment for < 80% of required days or take other treatments

Sample size

From the perspective of safety issues, according to our preliminary experiments, the effective rate in the sham-stimulation group was 15%, while in the FNS group was 55%. To test for significant differences between sham-stimulation and FNS groups, the significance level was α = 5% (two-sided), with the power being β = 90%.

According to the formula ,

u α and u β are u values corresponding to α and β, while p 1 and p 2 are the calculated frequency values for two samples, with p being the merged value of two sample frequencies. Accordingly, n = 28 was calculated. Taking into account a 'lost to follow-up' rate of 20%, n = 34 was calculated as the lowest sample size for each group. Therefore, n = 40 was used as the sample size for each group.

Recruitment

Migraine patients were recruited from five hospitals to participate in the trial through various public invitation methods including advertisements, posters, and leaflets. The invitation posters or leaflets were posted in the waiting room, rest room, and entrance of hospital buildings. Participants interested in participating in the trial contacted the person in charge by telephone or e-mail. After providing written informed consent, all potential participants were screened according to our inclusion and exclusion criteria.

Randomization

Eligible patients will be observed for 1 month for baseline collection prior to grouping. Patients suffering from two or more migraine attacks per month will be allocated to the FNS or sham-stimulation groups on a 1:1 ratio.

Blinding

Treatment allocation will not be disclosed until the end of the trial and will be performed according to the principle of block randomization. Noninvasive FNS equipment and sham-stimulation equipment look the same, and have the same manual and parameters. Therefore, FNS and sham-stimulation equipment cannot be distinguished.

Interventions

FNS group

After cleaning the skin, the stimulating electrode (Chongqing Haikun Medical Appliance Co., Ltd., Chongqing, China) will be positioned in the mastoid bone behind the ear. The size of the electrode is 42 mm × 24 mm with a conductive area of Φ19 mm ([Figure 2]). The stimulation parameters include: pulse width 90 μs, frequency 1.8 kHz, and output current 10 mA. Participants will receive FNS once a day for 45 minutes, for 3 successive days.

Figure 2: Position of the stimulation electrode placed on the mastoid area behind the ear

The sham-stimulation parameters include: pulse width 90 μs, frequency 10 Hz, and output current 0.18 mA. Participants will receive FNS once a day for 45 minutes, for 3 successive days.

Outcome measures

Primary outcome measures

Change in monthly migraine days between the run-in month and 3 rd month of treatment; and 50% response rate, i.e., percentage of patients having at least a 50% reduction of monthly migraine days in the 3 rd month of treatment.

Secondary outcome measures

(1) Change in average monthly migraine days across 3 months of treatment.

(2) Monthly migraine days in the 3 rd month of treatment.

(3) Severity of migraine as determined by the visual analogue scale (VAS) score, with score 0 indicating no pain and score 10 representing most pain (Collins et al., 1997), in the 3 rd month of treatment; accompanying symptoms include migraine aura, nausea/vomiting, extreme sensitivity to light, sounds, or smells, and use of analgesics.

(4) Change in monthly anti-migraine drug use between the run-in month and 3 rd month of treatment.

(5) Migraine disability assessment (MIDAS) questionnaire score. The questionnaire is designed to examine headache-caused disability in working and daily life. The questionnaire score is calculated by the sum of days in the last 3 months in which the patient missed work or school; did not perform household work; missed family, social, or leisure activities; or experienced a reduction in work or school productivity by half or more because of headache (Stewart et al., 1999).

(6) Adverse reactions including local skin irritation, pain, or other discomfort.

Patient's baseline characteristics are shown in [Table 2] and the schedule for outcome assessments is shown in [Table 3].

Two persons will not participate in recruitment of participants, and will be responsible for collecting patients' migraine diaries (containing number of FNS applications and duration of a single stimulation, and which will be completed by the patients themselves), and creating a database. During treatment, patients will be followed up once per month. After blinded auditing and collation, the created database will be locked by the researcher in charge and will not be altered. All information relating to this trial will be stored by Chengdu Second People's Hospital. The electronic database will be fully disclosed to a professional statistician for statistical analysis, and the results reported to the researcher in charge. An independent data-monitoring committee will monitor data collection and management to ensure a scientific, rigorous, real, and complete research process. Anonymized trial data will be published at http://www.figshare.com.

Statistical analysis

All data will be statistically analyzed using SPSS 11.5 software. Accompanying symptoms and adverse reactions will be expressed as percentages and tested using the chi-square test. The remaining results will be expressed as the mean ± SD. The Mann-Whiney U test will be used for comparisons of primary and secondary outcome measures between FNS and sham-stimulation groups. The non-parametric Sign test will be used for comparisons of monthly changes in indices between the 3 rd month of treatment and run-in month, as well as between average outcomes across 3 months and the run-in month. A level of P < 0.05 will be considered statistically significant.

Auditing

Trial progression will be reported to the ethics committee of Chengdu Second People's Hospital, China every 6-12 months, and the trial status updated in the registration database.

Confidentiality

All information relating to this trial will be stored in a secure, locked place for future viewing, and not disclosed to any non-authorized person. Researchers participating in this trial will adhere to the confidentiality and privacy agreements.

Discussion

In this trial, to reduce the body surface sensation of current stimulation, intermediate frequency peak currents will be superimposed, with the largest current peak being 10 mA, and leading to a current change of 1-1.2 mA. This low-frequency signal will be modulated within 13-45 Hz. Within this frequency range, current change and modulated signal do not cause an obvious body surface sensation of current stimulation, and only a slight squeezing sensation is felt. The intermediate frequency signal is an exponential decay signal, with 'a' (0 < a < 1) as the base. Nonpolar differential exponential waveform is composed of positive and negative pulse waves with equal charge. Negative exponential pulses play a role in nerve fiber depolarization, while positive pulses have a charge-balancing role, resulting in an ingested static charge of 0 and leading to the lowest production of electrical stimulation-caused adverse electrochemical reactions. To reduce single pulse energy, under the condition of a constant pulse width of 90 μs, reduced base value accelerates decay and alleviates the squeezing sensation. When subjected to sham-stimulation, a patient's body surface sensation will be periodically point-touch sensitive. Therefore, patients and physicians cannot distinguish between FNS and sham-stimulation, which ensures double-blinded clinical significance of the results. Thus, our results will clarify the efficacy of daily FNS treatment in the prevention of migraine, and objectively provide effective theoretical evidence for the clinical application of FNS.

Trial status

Data summary and statistical analysis are undergoing at the time of submission.[52]

Conflicts of interest
None declared.Author contributions
JW conceive and design the trial protocol. SO, JZ, WWD and JHL are the head of each trial center. JY write the manuscript. All authors approve the final version of this manuscript for publication. Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication. Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.